Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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46 pages, 24845 KiB  
Review
Technologies for Direct Detection of Covalent Protein–Drug Adducts
by Elma Mons, Robbert Q. Kim and Monique P. C. Mulder
Pharmaceuticals 2023, 16(4), 547; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16040547 - 5 Apr 2023
Cited by 6 | Viewed by 5628
Abstract
In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and [...] Read more.
In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein–drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein–drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery. Full article
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19 pages, 705 KiB  
Review
Efficacy, Tolerability, and Safety of Toludesvenlafaxine for the Treatment of Major Depressive Disorder—A Narrative Review
by Octavian Vasiliu
Pharmaceuticals 2023, 16(3), 411; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030411 - 8 Mar 2023
Cited by 8 | Viewed by 5399
Abstract
The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached [...] Read more.
The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached clinical use. The objective of this narrative review was to summarize clinical and preclinical evidence about the efficacy, tolerability, and safety of toludesvenlafaxine. Based on the results of 17 reports retrieved in the literature, the safety and tolerability profiles of toludesvenlafaxine were good in all clinical trials, and the pharmacokinetic parameters were well described in the phase 1 trials. The efficacy of toludesvenlafaxine was demonstrated in one phase 2 and one phase 3 trial, both on primary and secondary outcomes. In conclusion, this review highlights the favorable clinical results of toludesvenlafaxine in only two short-term trials that enrolled patients with major depressive disorder (MDD) (efficacy and tolerability were good for up to eight weeks), indicating the need for more good quality, larger-sample, and longer-term trials. Exploring new antidepressants, such as TRI, can be considered a priority for clinical research due to the high rates of TRD, but also due to the significant percentages of relapse in patients with MDD. Full article
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16 pages, 1221 KiB  
Review
Current Trends in Neoantigen-Based Cancer Vaccines
by Szu-Ying Ho, Che-Mai Chang, Hsin-Ni Liao, Wan-Hsuan Chou, Chin-Lin Guo, Yun Yen, Yusuke Nakamura and Wei-Chiao Chang
Pharmaceuticals 2023, 16(3), 392; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030392 - 5 Mar 2023
Cited by 7 | Viewed by 4950
Abstract
Cancer immunotherapies are treatments that use drugs or cells to activate patients’ own immune systems against cancer cells. Among them, cancer vaccines have recently been rapidly developed. Based on tumor-specific antigens referred to as neoantigens, these vaccines can be in various forms such [...] Read more.
Cancer immunotherapies are treatments that use drugs or cells to activate patients’ own immune systems against cancer cells. Among them, cancer vaccines have recently been rapidly developed. Based on tumor-specific antigens referred to as neoantigens, these vaccines can be in various forms such as messenger (m)RNA and synthetic peptides to activate cytotoxic T cells and act with or without dendritic cells. Growing evidence suggests that neoantigen-based cancer vaccines possess a very promising future, yet the processes of immune recognition and activation to relay identification of a neoantigen through the histocompatibility complex (MHC) and T-cell receptor (TCR) remain unclear. Here, we describe features of neoantigens and the biological process of validating neoantigens, along with a discussion of recent progress in the scientific development and clinical applications of neoantigen-based cancer vaccines. Full article
(This article belongs to the Section Pharmacology)
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49 pages, 23991 KiB  
Review
Fluorescent Probes as a Tool in Diagnostic and Drug Delivery Systems
by Nikolai I. Georgiev, Ventsislav V. Bakov, Kameliya K. Anichina and Vladimir B. Bojinov
Pharmaceuticals 2023, 16(3), 381; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030381 - 1 Mar 2023
Cited by 20 | Viewed by 5637
Abstract
Over the last few years, the development of fluorescent probes has received considerable attention. Fluorescence signaling allows noninvasive and harmless real-time imaging with great spectral resolution in living objects, which is extremely useful for modern biomedical applications. This review presents the basic photophysical [...] Read more.
Over the last few years, the development of fluorescent probes has received considerable attention. Fluorescence signaling allows noninvasive and harmless real-time imaging with great spectral resolution in living objects, which is extremely useful for modern biomedical applications. This review presents the basic photophysical principles and strategies for the rational design of fluorescent probes as visualization agents in medical diagnosis and drug delivery systems. Common photophysical phenomena, such as Intramolecular Charge Transfer (ICT), Twisted Intramolecular Charge Transfer (TICT), Photoinduced Electron Transfer (PET), Excited-State Intramolecular Proton Transfer (ESIPT), Fluorescent Resonance Energy Transfer (FRET), and Aggregation-Induced Emission (AIE), are described as platforms for fluorescence sensing and imaging in vivo and in vitro. The presented examples are focused on the visualization of pH, biologically important cations and anions, reactive oxygen species (ROS), viscosity, biomolecules, and enzymes that find application for diagnostic purposes. The general strategies regarding fluorescence probes as molecular logic devices and fluorescence–drug conjugates for theranostic and drug delivery systems are discussed. This work could be of help for researchers working in the field of fluorescence sensing compounds, molecular logic gates, and drug delivery. Full article
(This article belongs to the Special Issue Fluorescence Approaches in Drug Delivery)
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61 pages, 15468 KiB  
Review
Asymmetric Synthesis of US-FDA Approved Drugs over Five Years (2016–2020): A Recapitulation of Chirality
by Rekha Tamatam and Dongyun Shin
Pharmaceuticals 2023, 16(3), 339; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030339 - 22 Feb 2023
Cited by 5 | Viewed by 5227
Abstract
Chirality is a major theme in the design, discovery, and development of new drugs. Historically, pharmaceuticals have been synthesized as racemic mixtures. However, the enantiomeric forms of drug molecules have distinct biological properties. One enantiomer may be responsible for the desired therapeutic effect [...] Read more.
Chirality is a major theme in the design, discovery, and development of new drugs. Historically, pharmaceuticals have been synthesized as racemic mixtures. However, the enantiomeric forms of drug molecules have distinct biological properties. One enantiomer may be responsible for the desired therapeutic effect (eutomer), whereas the other may be inactive, interfere with the therapeutic form, or exhibit toxicity (distomer). Classical chemical synthesis usually leads to a racemic mixture unless stereospecific synthesis is employed. To meet the requirements of single-enantiomeric drugs, asymmetric synthesis has evolved at the forefront of drug discovery. Asymmetric synthesis involves the conversion of an achiral starting material into a chiral product. This review emphasizes the methods used for synthesizing FDA-approved chiral drugs during 2016–2020, with a special focus on asymmetric synthesis by means of chiral induction, resolution, or chiral pool. Full article
(This article belongs to the Section Medicinal Chemistry)
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19 pages, 3755 KiB  
Review
Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development
by Chia-Ju Hsieh, Sam Giannakoulias, E. James Petersson and Robert H. Mach
Pharmaceuticals 2023, 16(2), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020317 - 18 Feb 2023
Cited by 8 | Viewed by 3887
Abstract
The use of computer-aided drug design (CADD) for the identification of lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening and optimization, have been successfully utilized in many drug discovery programs and are highlighted [...] Read more.
The use of computer-aided drug design (CADD) for the identification of lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening and optimization, have been successfully utilized in many drug discovery programs and are highlighted throughout this review. First, we discuss the use of virtual screening for hit identification at the beginning of drug discovery programs. This is followed by an analysis of how the hits derived from virtual screening can be filtered and culled to highly probable candidates to test in in vitro assays. We then illustrate how CADD can be used to optimize the potency of experimentally validated hit compounds from virtual screening for use in positron emission tomography (PET). Finally, we conclude with a survey of the newest techniques in CADD employing machine learning (ML). Full article
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21 pages, 1640 KiB  
Review
Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy
by Liesbeth Everix, Elsie Neo Seane, Thomas Ebenhan, Ingeborg Goethals and Julie Bolcaen
Pharmaceuticals 2023, 16(2), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020227 - 1 Feb 2023
Cited by 9 | Viewed by 2831
Abstract
Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA [...] Read more.
Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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23 pages, 1132 KiB  
Review
Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer
by Charnay Cunningham, Julie Bolcaen, Alessandra Bisio, Amanda Genis, Hans Strijdom and Charlot Vandevoorde
Pharmaceuticals 2023, 16(2), 219; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020219 - 31 Jan 2023
Cited by 4 | Viewed by 3238
Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in [...] Read more.
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer, which is the leading cause of cancer-related deaths worldwide. Over the past decades, tumour angiogenesis has been intensely studied in the treatment of NSCLC due to its fundamental role in cancer progression. Several anti-angiogenic drugs, such as recombinant endostatin (RE), have been evaluated in several preclinical and clinical trials, with mixed and often disappointing results. However, there is currently an emerging interest in RE due to its ability to create a vascular normalization window, which could further improve treatment efficacy of the standard NSCLC treatment. This review provides an overview of preclinical and clinical studies that combined RE and radiotherapy for NSCLC treatment. Furthermore, it highlights the ongoing challenges that have to be overcome in order to maximize the benefit; as well as the potential advantage of combinations with particle therapy and immunotherapy, which are rapidly gaining momentum in the treatment landscape of NSCLC. Different angiogenic and immunosuppressive effects are observed between particle therapy and conventional X-ray radiotherapy. The combination of RE, particle therapy and immunotherapy presents a promising future therapeutic triad for NSCLC. Full article
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22 pages, 1691 KiB  
Review
Role and Mechanisms of Phytochemicals in Hair Growth and Health
by Periyanaina Kesika, Bhagavathi Sundaram Sivamaruthi, Subramanian Thangaleela, Muruganantham Bharathi and Chaiyavat Chaiyasut
Pharmaceuticals 2023, 16(2), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020206 - 30 Jan 2023
Cited by 7 | Viewed by 16423
Abstract
Hair health is associated with personal distress and psychological well-being. Even though hair loss (alopecia) does not affect humans’ biological health, it affects an individual’s social well-being. So, treatment for hair problems and improving hair health are obligatory. Several pharmacological and cosmeceutical treatment [...] Read more.
Hair health is associated with personal distress and psychological well-being. Even though hair loss (alopecia) does not affect humans’ biological health, it affects an individual’s social well-being. So, treatment for hair problems and improving hair health are obligatory. Several pharmacological and cosmeceutical treatment procedures are available to manage hair loss and promote growth. Several factors associated with hair health include genetics, disease or disorder, drugs, lifestyle, chemical exposure, and unhealthy habits such as smoking, diet, and stress. Synthetic and chemical formulations have side effects, so people are moving towards natural compounds-based remedies for their hair problems. The history of using phytochemicals for hair health has been documented anciently. However, scientific studies on hair loss have accelerated in recent decades. The current review summarizes the type of alopecia, the factor affecting hair health, alopecia treatments, phytochemicals’ role in managing hair loss, and the mechanisms of hair growth-stimulating properties of phytochemicals. The literature survey suggested that phytochemicals are potent candidates for developing treatment procedures for different hair problems. Further detailed studies are needed to bring the scientific evidence to market. Full article
(This article belongs to the Special Issue Feature Reviews in Natural Products)
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25 pages, 1640 KiB  
Review
Potential of Lactoferrin in the Treatment of Lung Diseases
by Katarzyna Kaczyńska, Monika Jampolska, Piotr Wojciechowski, Dorota Sulejczak, Kryspin Andrzejewski and Dominika Zając
Pharmaceuticals 2023, 16(2), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020192 - 28 Jan 2023
Cited by 6 | Viewed by 3848
Abstract
Lactoferrin (LF) is a multifunctional iron-binding glycoprotein that exhibits a variety of properties, such as immunomodulatory, anti-inflammatory, antimicrobial, and anticancer, that can be used to treat numerous diseases. Lung diseases continue to be the leading cause of death and disability worldwide. Many of [...] Read more.
Lactoferrin (LF) is a multifunctional iron-binding glycoprotein that exhibits a variety of properties, such as immunomodulatory, anti-inflammatory, antimicrobial, and anticancer, that can be used to treat numerous diseases. Lung diseases continue to be the leading cause of death and disability worldwide. Many of the therapies currently used to treat these diseases have limited efficacy or are associated with side effects. Therefore, there is a constant pursuit for new drugs and therapies, and LF is frequently considered a therapeutic agent and/or adjunct to drug-based therapies for the treatment of lung diseases. This article focuses on a review of the existing and most up-to-date literature on the contribution of the beneficial effects of LF on the treatment of lung diseases, including asthma, viral infections, cystic fibrosis, or lung cancer, among others. Although in vitro and in vivo studies indicate significant potency of LF in the treatment of the listed diseases, only in the case of respiratory tract infections do human studies seem to confirm them by demonstrating the effectiveness of LF in reducing episodes of illness and shortening the recovery period. For lung cancer, COVID-19 and sepsis, the reports are conflicting, and for other diseases, there is a paucity of human studies conclusively confirming the beneficial effects of LF. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Lactoferrin)
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13 pages, 2515 KiB  
Article
Cytotoxic and Antileishmanial Effects of the Monoterpene β-Ocimene
by Julyanne Maria Saraiva de Sousa, Thaís Amanda de Lima Nunes, Raiza Raianne Luz Rodrigues, João Paulo Araújo de Sousa, Maria da Conceição Albuquerque Val, Francisco Alex da Rocha Coelho, Airton Lucas Sousa dos Santos, Nicolle Barreira Maciel, Vanessa Maria Rodrigues de Souza, Yasmim Alves Aires Machado, Paulo Sérgio de Araújo Sousa, Alyne Rodrigues de Araújo, Jefferson Almeida Rocha, Damião Pergentino de Sousa, Marcos Vinicius da Silva, Daniel Dias Rufino Arcanjo and Klinger Antônio da Franca Rodrigues
Pharmaceuticals 2023, 16(2), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020183 - 26 Jan 2023
Cited by 13 | Viewed by 3336
Abstract
Leishmaniasis is a group of infectious-parasitic diseases with high mortality rates, and endemic in many regions of the globe. The currently available drugs present serious problems such as high toxicity, costs, and the emergence of drug resistance. This has stimulated research into new [...] Read more.
Leishmaniasis is a group of infectious-parasitic diseases with high mortality rates, and endemic in many regions of the globe. The currently available drugs present serious problems such as high toxicity, costs, and the emergence of drug resistance. This has stimulated research into new antileishmania drugs based on natural products and their derivatives. β-Ocimene is a monoterpene found naturally in the essential oils of many plant species which presents antileishmanial activity, and which has not yet been evaluated for its potential to inhibit the etiological agent of leishmaniasis. The aim of this work was to evaluate the activity of β-ocimene against Leishmania amazonensis, its cytotoxicity, and potential mechanisms of action. β-Ocimene presented direct activity against the parasite, with excellent growth inhibition of promastigotes (IC50 = 2.78 μM) and axenic amastigotes (EC50 = 1.12 μM) at concentrations non-toxic to RAW 264.7 macrophages (CC50 = 114.5 µM). The effect is related to changes in membrane permeability and resulting abnormalities in the parasitic cell shape. These were, respectively, observed in membrane integrity and atomic force microscopy assays. β-Ocimene was also shown to act indirectly, with greater activity against intra-macrophagic amastigotes (EC50 = 0.89 μM), increasing TNF-α, nitric oxide (NO), and reactive oxygen species (ROS), with lysosomal effects, as well as promoting decreases in IL-10 and IL-6. Against intra-macrophagic amastigote forms the selectivity index was higher than the reference drugs, being 469.52 times more selective than meglumine antimoniate, and 42.88 times more selective than amphotericin B. Our results suggest that β-ocimene possesses promising in vitro antileishmania activity and is a potential candidate for investigation in in vivo assays. Full article
(This article belongs to the Section Natural Products)
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21 pages, 2706 KiB  
Article
Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant Klebsiella pneumoniae
by Declan Byrnes, Claire H. Masterson, Jack Brady, Senthilkumar Alagesan, Hector E. Gonzalez, Sean D. McCarthy, Juan Fandiño, Daniel P. O’Toole and John G. Laffey
Pharmaceuticals 2023, 16(2), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020149 - 19 Jan 2023
Cited by 2 | Viewed by 2232
Abstract
Background: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established Klebsiella pneumoniae pneumosepsis and further evaluated [...] Read more.
Background: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established Klebsiella pneumoniae pneumosepsis and further evaluated MSC preconditioning and pre-activation methods. Methods: The potential for naïve and preconditioned MSCs to enhance wound healing, reduce inflammation, preserve metabolic activity, and enhance bacterial killing was assessed in vitro. Rats were subjected to intratracheal K. pneumoniae followed by the intravenous administration of MSCs. Physiological indices, blood, bronchoalveolar lavage (BAL), and tissues were obtained 72 h later. Results: In vitro assays confirmed that preconditioning enhances MSC function, accelerating pulmonary epithelial wound closure, reducing inflammation, attenuating cell death, and increasing bacterial killing. Cytomix-pre-activated MSCs are superior to naïve and hypoxia-exposed MSCs in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, reducing bacteria, and attenuating histologic injuries in lungs. BAL inflammatory cytokines were reduced, correlating with decreases in polymorphonuclear (PMN) cells. MSCs increased PMN apoptosis and the CD4:CD8 ratio in BAL. Systemically, granulocytes, classical monocytes, and the CD4:CD8 ratio were reduced, and nonclassical monocytes were increased. Conclusions: Preconditioning with cytokines, but not hypoxia, enhances the therapeutic potential of MSCs in clinically relevant models of K. pneumoniae-induced pneumosepsis. Full article
(This article belongs to the Special Issue New Advances in Mesenchymal Stromal Cells as Therapeutic Tools)
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23 pages, 3179 KiB  
Article
N-Derivatives of (Z)-Methyl 3-(4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylates as Antimicrobial Agents—In Silico and In Vitro Evaluation
by Anthi Petrou, Athina Geronikaki, Victor Kartsev, Antonios Kousaxidis, Aliki Papadimitriou-Tsantarliotou, Marina Kostic, Marija Ivanov, Marina Sokovic, Ioannis Nicolaou and Ioannis S. Vizirianakis
Pharmaceuticals 2023, 16(1), 131; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010131 - 16 Jan 2023
Cited by 4 | Viewed by 2238
Abstract
Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by [...] Read more.
Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by 10–50 fold. The most sensitive bacterium was En. Cloacae, while E. coli was the most resistant one, followed by M. flavus. The most active compound appeared to be compound 8 with MIC at 0.004–0.03 mg/mL and MBC at 0.008–0.06 mg/mL. The antifungal activity of tested compounds was good to excellent with MIC in the range of 0.004–0.06 mg/mL, with compound 15 being the most potent. T. viride was the most sensitive fungal, while A. fumigatus was the most resistant one. Docking studies revealed that the inhibition of E. coli MurB is probably responsible for their antibacterial activity, while 14a–lanosterol demethylase of CYP51Ca is involved in the mechanism of antifungal activity. Furthermore, drug-likeness and ADMET profile prediction were performed. Finally, the cytotoxicity studies were performed for the most active compounds using MTT assay against normal MRC5 cells. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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17 pages, 1181 KiB  
Review
Prolactin Relationship with Fertility and In Vitro Fertilization Outcomes—A Review of the Literature
by Mirela E. Iancu, Alice I. Albu and Dragoș N. Albu
Pharmaceuticals 2023, 16(1), 122; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010122 - 13 Jan 2023
Cited by 2 | Viewed by 8866
Abstract
Hyperprolactinemia is a known cause of amenorrhea and infertility. However, there is an increasing body of evidence suggesting that prolactin is involved in multiple physiological aspects of normal reproduction. Thus, the present paper aims to review the current literature regarding the relationship between [...] Read more.
Hyperprolactinemia is a known cause of amenorrhea and infertility. However, there is an increasing body of evidence suggesting that prolactin is involved in multiple physiological aspects of normal reproduction. Thus, the present paper aims to review the current literature regarding the relationship between serum prolactin level and in vitro fertilization (IVF)/intracytoplasmic sperm injection outcome and the role of dopamine agonists treatment in IVF success. Moreover, the mechanisms by which prolactin may exert its role in fertility and infertility were summarized. Although not all studies agree, the available evidence suggests that higher prolactin levels in follicular fluid are associated with increased oocytes competence, but also with positive effects on corpus luteum formation and survival, endometrial receptivity, blastocyst implantation potential and survival of low-motile sperm. Transient hyperprolactinemia found in IVF cycles was reported in most of the studies not to be related to IVF outcome, although a few reports suggested that it may be associated with higher implantation and pregnancy rates, and better-cumulated pregnancy outcomes. Administration of dopamine agonists for hyperprolactinemia preceding IVF treatment does not seem to negatively impact the IVF results, while treatment of transient hyperprolactinemia during IVF might be beneficial in terms of fertilization rates and conception rates. Due to limited available evidence, future studies are necessary to clarify the optimal level of circulating prolactin in patients performing IVF and the role of dopamine agonist treatment. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 3550 KiB  
Article
Numerical and Machine Learning Analysis of the Parameters Affecting the Regionally Delivered Nasal Dose of Nano- and Micro-Sized Aerosolized Drugs
by Ali Farnoud, Hesam Tofighian, Ingo Baumann, Kaveh Ahookhosh, Oveis Pourmehran, Xinguang Cui, Vincent Heuveline, Chen Song, Sarah Vreugde, Peter-John Wormald, Michael P. Menden and Otmar Schmid
Pharmaceuticals 2023, 16(1), 81; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010081 - 6 Jan 2023
Cited by 3 | Viewed by 3949
Abstract
The nasal epithelium is an important target for drug delivery to the nose and secondary organs such as the brain via the olfactory bulb. For both topical and brain delivery, the targeting of specific nasal regions such as the olfactory epithelium (brain) is [...] Read more.
The nasal epithelium is an important target for drug delivery to the nose and secondary organs such as the brain via the olfactory bulb. For both topical and brain delivery, the targeting of specific nasal regions such as the olfactory epithelium (brain) is essential, yet challenging. In this study, a numerical model was developed to predict the regional dose as mass per surface area (for an inhaled mass of 2.5 mg), which is the biologically most relevant dose metric for drug delivery in the respiratory system. The role of aerosol diameter (particle diameter: 1 nm to 30 µm) and inhalation flow rate (4, 15 and 30 L/min) in optimal drug delivery to the vestibule, nasal valve, olfactory and nasopharynx is assessed. To obtain the highest doses in the olfactory region, we suggest aerosols with a diameter of 20 µm and a medium inlet air flow rate of 15 L/min. High deposition on the olfactory epithelium was also observed for nanoparticles below 1 nm, as was high residence time (slow flow rate of 4 L/min), but the very low mass of 1 nm nanoparticles is prohibitive for most therapeutic applications. Moreover, high flow rates (30 L/min) and larger micro-aerosols lead to highest doses in the vestibule and nasal valve regions. On the other hand, the highest drug doses in the nasopharynx are observed for nano-aerosol (1 nm) and fine microparticles (1–20 µm) with a relatively weak dependence on flow rate. Furthermore, using the 45 different inhalation scenarios generated by numerical models, different machine learning models with five-fold cross-validation are trained to predict the delivered dose and avoid partial differential equation solvers for future predictions. Random forest and gradient boosting models resulted in R2 scores of 0.89 and 0.96, respectively. The aerosol diameter and region of interest are the most important features affecting delivered dose, with an approximate importance of 42% and 47%, respectively. Full article
(This article belongs to the Special Issue Recent Advances on Acoustic, Ultrasonic, and Magnetic Drug Delivery)
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15 pages, 1852 KiB  
Article
Development and Validation of a Non-Targeted Screening Method for Most Psychoactive, Analgesic, Anaesthetic, Anti-Diabetic, Anti-Coagulant and Anti-Hypertensive Drugs in Human Whole Blood and Plasma Using High-Resolution Mass Spectrometry
by Catherine Feliu, Celine Konecki, Yoann Cazaubon, Laurent Binet, Damien Vautier, Aurélie Fouley, Claire Gozalo and Zoubir Djerada
Pharmaceuticals 2023, 16(1), 76; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010076 - 4 Jan 2023
Cited by 4 | Viewed by 3068
Abstract
(1) Background: In toxicological laboratories, various screening methods can be used to identify compounds involved in intoxication. High-resolution mass spectrometry has been increasingly used in this context for the last years, because of its sensitivity and reliability. Here, we present the development and [...] Read more.
(1) Background: In toxicological laboratories, various screening methods can be used to identify compounds involved in intoxication. High-resolution mass spectrometry has been increasingly used in this context for the last years, because of its sensitivity and reliability. Here, we present the development and validation of a screening method that uses liquid chromatography coupled with a high-resolution mass spectrometer. (2) Methods: This method required only 100 µL of whole blood or plasma sample. Pretreatment consisted of a rapid and simple deproteinisation with methanol/acetonitrile and zinc sulphate. This new assay was validated according to international guidelines. (3) Results: To perform the method validation, 53 compounds were selected. The selection criteria were as follows: various chemical structures and therapeutic families (>15), large m/z distribution, positive or negative ionisation mode, and various elution times. The assays showed high selectivity and specificity, with optimal process efficiency. The identification limits, determined using predefined criteria, were established at sub-therapeutic or therapeutic concentrations. Applicability was evaluated using spiked plasma controls and external quality controls. (4) Conclusions: The new method was then successfully applied to routine clinical and forensic samples. Full article
(This article belongs to the Section Medicinal Chemistry)
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17 pages, 2339 KiB  
Article
Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain
by Anniina T. Virtanen, Teemu Haikarainen, Parthasarathy Sampathkumar, Maaria Palmroth, Sanna Liukkonen, Jianping Liu, Natalia Nekhotiaeva, Stevan R. Hubbard and Olli Silvennoinen
Pharmaceuticals 2023, 16(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16010075 - 4 Jan 2023
Cited by 6 | Viewed by 4307
Abstract
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted [...] Read more.
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of the JAK2 JH2 ATP-binding pocket. Selected hits and structural analogs were further assessed for binding to JH2 and JH1 (kinase) domains of JAK family members (JAK1-3, TYK2) and for effects on MPN model cell viability. Crystal structures were determined with JAK2 JH2 wild-type and V617F. The JH2-selective binders were identified in diaminotriazole, diaminotriazine, and phenylpyrazolo-pyrimidone chemical entities, but they showed low-affinity, and no inhibition of MPN cells was detected, while compounds binding to both JAK2 JH1 and JH2 domains inhibited MPN cell viability. X-ray crystal structures of protein-ligand complexes indicated generally similar binding modes between the ligands and V617F or wild-type JAK2. Ligands of JAK2 JH2 V617F are applicable as probes in JAK-STAT research, and SAR optimization combined with structural insights may yield higher-affinity inhibitors with biological activity. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
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16 pages, 3527 KiB  
Article
Hydroxysafflor Yellow A Phytosomes Administered via Intervaginal Space Injection Ameliorate Pulmonary Fibrosis in Mice
by Tingting Li, Dong Han, Zhongxian Li, Mengqi Qiu, Yuting Zhu, Kai Li, Jiawei Xiang, Huizhen Sun, Yahong Shi, Tun Yan, Xiaoli Shi and Qiang Zhang
Pharmaceuticals 2022, 15(11), 1394; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111394 - 12 Nov 2022
Cited by 2 | Viewed by 1554
Abstract
Idiopathic pulmonary fibrosis is a fatal interstitial disease characterized by fibroblast proliferation and differentiation and abnormal accumulation of extracellular matrix, with high mortality and an increasing annual incidence. Since few drugs are available for the treatment of pulmonary fibrosis, there is an urgent [...] Read more.
Idiopathic pulmonary fibrosis is a fatal interstitial disease characterized by fibroblast proliferation and differentiation and abnormal accumulation of extracellular matrix, with high mortality and an increasing annual incidence. Since few drugs are available for the treatment of pulmonary fibrosis, there is an urgent need for high-efficiency therapeutic drugs and treatment methods to reduce the mortality associated with pulmonary fibrosis. The interstitium, a highly efficient transportation system that pervades the body, plays an important role in the occurrence and development of disease, and can be used as a new route for disease diagnosis and treatment. In this study, we evaluated the administration of hydroxysafflor yellow A phytosomes via intervaginal space injection (ISI) as an anti-pulmonary fibrosis treatment. Our results show that this therapeutic strategy blocked the activation of p38 protein in the MAPK-p38 signaling pathway and inhibited the expression of Smad3 protein in the TGF-β/Smad signaling pathway, thereby reducing secretion of related inflammatory factors, deposition of collagen in the lungs of mice, and destruction of the alveolar structure. Use of ISI in the treatment of pulmonary fibrosis provides a potential novel therapeutic modality for the disease. Full article
(This article belongs to the Special Issue Drug Delivery to the Lungs: Challenges and Opportunities)
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15 pages, 2312 KiB  
Article
Association between Migraines and Prior Proton Pump Inhibitor Use: A Nested Case-Control Study Using a National Health Screening Cohort
by Ho Suk Kang, So Young Kim, Ji Hee Kim, Eun Soo Kim, Hyo Geun Choi, Hyun Lim, Joo-Hee Kim, Ha Young Park, Nan Young Kim, Sangkyoon Hong, Kyung Chan Choi and Mi Jung Kwon
Pharmaceuticals 2022, 15(11), 1385; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111385 - 10 Nov 2022
Cited by 3 | Viewed by 2042
Abstract
The effect of proton pump inhibitor (PPI) use on migraine risk remains controversial. We explored the odds of migraines in relation to prior PPI use and treatment duration. Data from the Korean National Health Insurance Service-Health Screening Cohort (2002–2015) were analyzed in this [...] Read more.
The effect of proton pump inhibitor (PPI) use on migraine risk remains controversial. We explored the odds of migraines in relation to prior PPI use and treatment duration. Data from the Korean National Health Insurance Service-Health Screening Cohort (2002–2015) were analyzed in this nested case-control study involving 28,159 participants with incident migraines and 112,636 controls (1:4 matched by sex, age, income, and residential region). The baseline covariates were balanced by performing propensity score overlap weighting-based adjustments, and the effect of prior PPI use (past vs. current) and treatment duration (<30 and 30–365 days vs. ≥365 days) on incident migraines was evaluated using logistic regression. In past and current PPI users, prior PPI use raised the likelihood of migraines (adjusted odds ratio [95% confidence interval]: 2.56 [2.36–2.79] and 4.66 [4.29–5.06], respectively). Participants who used PPI for <30, 30–365, or ≥365 days exhibited high odds of migraines (2.49 [2.29–2.72], 4.41 [4.05–4.79], and 4.14 [3.77–4.54], respectively). Incident migraines with or without aura also increased independently of PPI use history or duration. In summary, prior PPI use, irrespective of the elapsed time since use and the duration of use, is possibly associated with incident migraines with or without aura. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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22 pages, 1485 KiB  
Review
Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery
by Kirsten McAulay, Alan Bilsland and Marta Bon
Pharmaceuticals 2022, 15(11), 1366; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111366 - 8 Nov 2022
Cited by 15 | Viewed by 6191
Abstract
Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising [...] Read more.
Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be ‘undruggable’. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined. Full article
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15 pages, 1324 KiB  
Review
Synthesis and Biological Activities of Dehydrodiisoeugenol: A Review
by Beatriz Godínez-Chaparro, Salud Pérez-Gutiérrez, Julia Pérez-Ramos, Ivo Heyerdahl-Viau and Liliana Hernández-Vázquez
Pharmaceuticals 2022, 15(11), 1351; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111351 - 31 Oct 2022
Cited by 4 | Viewed by 1916
Abstract
Dehydrodiisoeugenol (DHIE) is a neolignan found in more than 17 plant species, including herbs, fruit, and root. DHIE was, for the first time, isolated from Myristica fragrans bark in 1973. Since then, many methodologies have been used for the obtention of DHIE, including [...] Read more.
Dehydrodiisoeugenol (DHIE) is a neolignan found in more than 17 plant species, including herbs, fruit, and root. DHIE was, for the first time, isolated from Myristica fragrans bark in 1973. Since then, many methodologies have been used for the obtention of DHIE, including classical chemistry synthesis using metal catalysts and biocatalytic synthesis; employing horseradish peroxidase; peroxidase from Cocos nucifera; laccase; culture cells of plants; and microorganisms. Increasing evidence has indicated that DHIE has a wide range of biological activities: anti-inflammatory, anti-oxidant, anti-cancerogenic, and anti-microbial properties. However, evidence in vivo and in human beings is still lacking to support the usefulness potential of DHIE as a therapeutic agent. This study’s review was created by searching for relevant DHIE material on websites such as Google Scholar, PubMed, SciFinder, Scholar, Science Direct, and others. This reviews the current state of knowledge regarding the different synthetical routes and biological applications of DHIE. Full article
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18 pages, 968 KiB  
Review
Recent Advances in Hepatocellular Carcinoma Treatment with Radionuclides
by Ruiqi Liu, Hong Li, Yihua Qiu, Hongguang Liu and Zhen Cheng
Pharmaceuticals 2022, 15(11), 1339; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111339 - 28 Oct 2022
Cited by 2 | Viewed by 2066
Abstract
As the third leading cause of cancer death worldwide, hepatocellular carcinoma (HCC) is characterized by late detection, difficult diagnosis and treatment, rapid progression, and poor prognosis. Current treatments for liver cancer include surgical resection, radiofrequency ablation, liver transplantation, chemotherapy, external radiation therapy, and [...] Read more.
As the third leading cause of cancer death worldwide, hepatocellular carcinoma (HCC) is characterized by late detection, difficult diagnosis and treatment, rapid progression, and poor prognosis. Current treatments for liver cancer include surgical resection, radiofrequency ablation, liver transplantation, chemotherapy, external radiation therapy, and internal radionuclide therapy. Radionuclide therapy is the use of high-energy radiation emitted by radionuclides to eradicate tumor cells, thus achieving the therapeutic effect. Recently, with the continuous development of biomedical technology, the application of radionuclides in treatment of HCC has progressed steadily. This review focuses on three types of radionuclide-based treatment regimens, including transarterial radioembolization (TARE), radioactive seed implantation, and radioimmunotherapy. Their research progress and clinical applications are summarized. The advantages, limitations, and clinical potential of radionuclide treatment of HCC are discussed. Full article
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14 pages, 4262 KiB  
Article
Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat
by Camille Lagard, Dominique Vodovar, Lucie Chevillard, Jacques Callebert, Fabien Caillé, Géraldine Pottier, Hao Liang, Patricia Risède, Nicolas Tournier and Bruno Mégarbane
Pharmaceuticals 2022, 15(10), 1254; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101254 - 12 Oct 2022
Cited by 6 | Viewed by 3859
Abstract
Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The [...] Read more.
Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)A receptors in vivo in the brain using positron emission tomography (PET) imaging and 11C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of 11C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABAA receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway. Full article
(This article belongs to the Special Issue Psychoactive Substances: Pharmacology and Toxicology)
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14 pages, 2130 KiB  
Article
Reservoir-Style Polymeric Drug Delivery Systems: Empirical and Predictive Models for Implant Design
by Linying Li, Chanhwa Lee, Daniela F. Cruz, Sai Archana Krovi, Michael G. Hudgens, Mackenzie L. Cottrell and Leah M. Johnson
Pharmaceuticals 2022, 15(10), 1226; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101226 - 3 Oct 2022
Viewed by 2491
Abstract
Controlled drug delivery systems can provide sustained release profiles, favorable pharmacokinetics, and improved patient adherence. Here, a reservoir-style implant comprising a biodegradable polymer, poly(ε-caprolactone) (PCL), was developed to deliver drugs subcutaneously. This work addresses a key challenge when designing these implantable drug delivery [...] Read more.
Controlled drug delivery systems can provide sustained release profiles, favorable pharmacokinetics, and improved patient adherence. Here, a reservoir-style implant comprising a biodegradable polymer, poly(ε-caprolactone) (PCL), was developed to deliver drugs subcutaneously. This work addresses a key challenge when designing these implantable drug delivery systems, namely the accurate prediction of drug release profiles when using different formulations or form factors of the implant. The ability to model and predict the release behavior of drugs from an implant based on their physicochemical properties enables rational design and optimization without extensive and laborious in vitro testing. By leveraging experimental observations, we propose a mathematical model that predicts the empirical parameters describing the drug diffusion and partitioning processes based on the physicochemical properties of the drug. We demonstrate that the model enables an adequate fit predicting empirical parameters close to experimental values for various drugs. The model was further used to predict the release performance of new drug formulations from the implant, which aligned with experimental results for implants exhibiting zero-order release kinetics. Thus, the proposed empirical models provide useful tools to inform the implant design to achieve a target release profile. Full article
(This article belongs to the Section Biopharmaceuticals)
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29 pages, 7356 KiB  
Article
Biocompatible, Multi-Mode, Fluorescent, T2 MRI Contrast Magnetoelectric-Silica Nanoparticles (MagSiNs), for On-Demand Doxorubicin Delivery to Metastatic Cancer Cells
by Margo Waters, Juliane Hopf, Emma Tam, Stephanie Wallace, Jordan Chang, Zach Bennett, Hadrian Aquino, Ryan K. Roeder, Paul Helquist, M. Sharon Stack and Prakash D. Nallathamby
Pharmaceuticals 2022, 15(10), 1216; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101216 - 30 Sep 2022
Cited by 3 | Viewed by 2482
Abstract
There is a need to improve current cancer treatment regimens to reduce systemic toxicity, to positively impact the quality-of-life post-treatment. We hypothesized the negation of off-target toxicity of anthracyclines (e.g., Doxorubicin) by delivering Doxorubicin on magneto-electric silica nanoparticles (Dox-MagSiNs) to cancer cells. Dox-MagSiNs [...] Read more.
There is a need to improve current cancer treatment regimens to reduce systemic toxicity, to positively impact the quality-of-life post-treatment. We hypothesized the negation of off-target toxicity of anthracyclines (e.g., Doxorubicin) by delivering Doxorubicin on magneto-electric silica nanoparticles (Dox-MagSiNs) to cancer cells. Dox-MagSiNs were completely biocompatible with all cell types and are therapeutically inert till the release of Doxorubicin from the MagSiNs at the cancer cells location. The MagSiNs themselves are comprised of biocompatible components with a magnetostrictive cobalt ferrite core (4–6 nm) surrounded by a piezoelectric fused silica shell of 1.5 nm to 2 nm thickness. The MagSiNs possess T2-MRI contrast properties on par with RESOVIST™ due to their cobalt ferrite core. Additionally, the silica shell surrounding the core was volume loaded with green or red fluorophores to fluorescently track the MagSiNs in vitro. This makes the MagSiNs a suitable candidate for trackable, drug nanocarriers. We used metastatic triple-negative breast cancer cells (MDAMB231), ovarian cancer cells (A2780), and prostate cancer cells (PC3) as our model cancer cell lines. Human umbilical vein endothelial cells (HUVEC) were used as control cell lines to represent blood-vessel cells that suffer from the systemic toxicity of Doxorubicin. In the presence of an external magnetic field that is 300× times lower than an MRI field, we successfully nanoporated the cancer cells, then triggered the release of 500 nM of doxorubicin from Dox-MagSiNs to successfully kill >50% PC3, >50% A2780 cells, and killed 125% more MDAMB231 cells than free Dox.HCl. In control HUVECs, the Dox-MagSiNs did not nanoporate into the HUVECS and did not exhibited any cytotoxicity at all when there was no triggered release of Dox.HCl. Currently, the major advantages of our approach are, (i) the MagSiNs are biocompatible in vitro and in vivo; (ii) the label-free nanoporation of Dox-MagSiNs into cancer cells and not the model blood vessel cell line; (iii) the complete cancellation of the cytotoxicity of Doxorubicin in the Dox-MagSiNs form; (iv) the clinical impact of such a nanocarrier will be that it will be possible to increase the current upper limit for cumulative-dosages of anthracyclines through multiple dosing, which in turn will improve the anti-cancer efficacy of anthracyclines. Full article
(This article belongs to the Section Pharmaceutical Technology)
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24 pages, 3517 KiB  
Article
Steviol Glycoside, L-Arginine, and Chromium(III) Supplementation Attenuates Abnormalities in Glucose Metabolism in Streptozotocin-Induced Mildly Diabetic Rats Fed a High-Fat Diet
by Jakub Michał Kurek, Ewelina Król, Halina Staniek and Zbigniew Krejpcio
Pharmaceuticals 2022, 15(10), 1200; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101200 - 28 Sep 2022
Cited by 6 | Viewed by 2787
Abstract
Stevia rebaudiana Bertoni and its glycosides are believed to exhibit several health-promoting properties. Recently, the mechanisms of the anti-diabetic effects of steviol glycosides (SG) have been the subject of intense research. The following study aims to evaluate the results of SG (stevioside (ST) [...] Read more.
Stevia rebaudiana Bertoni and its glycosides are believed to exhibit several health-promoting properties. Recently, the mechanisms of the anti-diabetic effects of steviol glycosides (SG) have been the subject of intense research. The following study aims to evaluate the results of SG (stevioside (ST) and rebaudioside A (RA)) combined with L-arginine (L-Arg) and chromium(III) (CrIII) supplementation in streptozotocin- (STZ) induced mild type 2 diabetic rats fed a high-fat diet (HFD), with particular emphasis on carbohydrate and lipid metabolisms. The experiment was carried out on 110 male Wistar rats, 100 of which were fed an HFD to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin to induce mild type 2 diabetes. After confirmation of hyperglycemia, the rats were divided into groups. Three groups served as controls: diabetic untreated, diabetic treated with metformin (300 mg/kg BW), and healthy group. Eight groups were fed an HFD enriched with stevioside or rebaudioside A (2500 mg/kg BW) combined with L-arginine (2000 or 4000 mg/kg BW) and Cr(III) (1 or 5 mg/kg BW) for six weeks. The results showed that supplementation with SG (ST and RA) combined with L-arg and Cr(III) could improve blood glucose levels in rats with mild type 2 diabetes. Furthermore, ST was more effective in improving blood glucose levels, insulin resistance indices, and very low-density lipoprotein cholesterol (VLDL-C) concentrations than RA. Although L-arg and Cr(III) supplementation did not independently affect most blood carbohydrate and lipid indices, it further improved some biomarkers when combined, particularly with ST. Notably, the beneficial impact of ST on the homeostatic model assessment–insulin resistance (HOMA-IR) and on the quantitative insulin-sensitivity check index (QUICKI) was strengthened when mixed with a high dose of L-arg, while its impact on antioxidant status was improved when combined with a high dose of Cr(III) in rats with mild type 2 diabetes. In conclusion, these results suggest that supplementary stevioside combined with L-arginine and Cr(III) has therapeutic potential for mild type 2 diabetes. However, further studies are warranted to confirm these effects in other experimental models and humans. Full article
(This article belongs to the Special Issue Therapeutic Mechanisms of Nature Products against Insulin Resistance)
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11 pages, 2622 KiB  
Article
Efficient Production of the PET Radionuclide 133La for Theranostic Purposes in Targeted Alpha Therapy Using the 134Ba(p,2n)133La Reaction
by Santiago Andrés Brühlmann, Martin Kreller, Hans-Jürgen Pietzsch, Klaus Kopka, Constantin Mamat, Martin Walther and Falco Reissig
Pharmaceuticals 2022, 15(10), 1167; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101167 - 21 Sep 2022
Cited by 11 | Viewed by 2809
Abstract
Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, 225Ac provides all necessary physical and chemical properties for a [...] Read more.
Targeted Alpha Therapy is a research field of highest interest in specialized radionuclide therapy. Over the last decades, several alpha-emitting radionuclides have entered and left research topics towards their clinical translation. Especially, 225Ac provides all necessary physical and chemical properties for a successful clinical application, which has already been shown by [225Ac]Ac-PSMA-617. While PSMA-617 carries the DOTA moiety as the complexing agent, the chelator macropa as a macrocyclic alternative provides even more beneficial properties regarding labeling and complex stability in vivo. Lanthanum-133 is an excellent positron-emitting diagnostic lanthanide to radiolabel macropa-functionalized therapeutics since 133La forms a perfectly matched theranostic pair of radionuclides with the therapeutic radionuclide 225Ac, which itself can optimally be complexed by macropa as well. 133La was thus produced by cyclotron-based proton irradiation of an enriched 134Ba target. The target (30 mg of [134Ba]BaCO3) was irradiated for 60 min at 22 MeV and 10–15 µA beam current. Irradiation side products in the raw target solution were identified and quantified: 135La (0.4%), 135mBa (0.03%), 133mBa (0.01%), and 133Ba (0.0004%). The subsequent workup and anion-exchange-based product purification process took approx. 30 min and led to a total amount of (1.2–1.8) GBq (decay-corrected to end of bombardment) of 133La, formulated as [133La]LaCl3. After the complete decay of 133La, a remainder of ca. 4 kBq of long-lived 133Ba per 100 MBq of 133La was detected and rated as uncritical regarding personal dose and waste management. Subsequent radiolabeling was successfully performed with previously published macropa-derived PSMA inhibitors at a micromolar range (quantitative labeling at 1 µM) and evaluated by radio-TLC and radio-HPLC analyses. The scale-up to radioactivity amounts that are needed for clinical application purposes would be easy to achieve by increasing target mass, beam current, and irradiation time to produce 133La of high radionuclide purity (>99.5%) regarding labeling properties and side products. Full article
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11 pages, 2419 KiB  
Article
The Synthetic Cannabinoid URB447 Exerts Antitumor and Antimetastatic Effect in Melanoma and Colon Cancer
by Aitor Benedicto, Beatriz Arteta, Andrea Duranti and Daniel Alonso-Alconada
Pharmaceuticals 2022, 15(10), 1166; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101166 - 20 Sep 2022
Cited by 7 | Viewed by 2267
Abstract
The endocannabinoid system is widespread through the body and carries out a wide variety of functions. However, its involvement in other pathologies, such as cancer, still needs further attention. We aim to investigate the role of CB2 receptor during melanoma and colorectal cancer [...] Read more.
The endocannabinoid system is widespread through the body and carries out a wide variety of functions. However, its involvement in other pathologies, such as cancer, still needs further attention. We aim to investigate the role of CB2 receptor during melanoma and colorectal cancer (CRC) aggressiveness and metastatic growth in the liver. We used the synthetic cannabinoid URB447, a known CB2 agonist and CB1 antagonist drug, and studied prometastatic ability of mouse B16 melanoma and MCA38 CRC cells, by means of proliferation, apoptosis, cell cycle, migration and matrix degradation in vitro upon URB447 treatment. We reported a dose-dependent viability decrease in both tumor types. This result is partly mediated by apoptotic cell death and cell cycle arrest in G1/G0 phase, as observed through flow cytometry. Melanoma and CRC cell migration was affected in a dose-dependent fashion as observed through scratch assay, whereas the secretion of matrix degrading proteins metalloprotease 2 (MMP2) and 9 (MMP9) in tumor cells did not significantly change. Moreover, daily treatment of tumor bearing mice with URB447 decreased the development of liver metastasis in a melanoma model in vivo. This proof of concept study points out to the synthetic cannabinoid URB447 as a potential candidate for deeper studies to confirm its potential as antitumor therapy and liver metastasis treatment for CRC and melanoma. Full article
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12 pages, 2372 KiB  
Article
Applications of the Novel Quantitative Pharmacophore Activity Relationship Method QPhAR in Virtual Screening and Lead-Optimisation
by Stefan Michael Kohlbacher, Matthias Schmid, Thomas Seidel and Thierry Langer
Pharmaceuticals 2022, 15(9), 1122; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091122 - 8 Sep 2022
Cited by 3 | Viewed by 1860
Abstract
Pharmacophores are an established concept for the modelling of ligand–receptor interactions based on the abstract representations of stereoelectronic molecular features. They became widely popular as filters for the fast virtual screening of large compound libraries. A lot of effort has been put into [...] Read more.
Pharmacophores are an established concept for the modelling of ligand–receptor interactions based on the abstract representations of stereoelectronic molecular features. They became widely popular as filters for the fast virtual screening of large compound libraries. A lot of effort has been put into the development of sophisticated algorithms and strategies to increase the computational efficiency of the screening process. However, hardly any focus has been put on the development of automated procedures that optimise pharmacophores towards higher discriminatory power, which still has to be done manually by a human expert. In the age of machine learning, the researcher has become the decision-maker at the top level, outsourcing analysis tasks and recurrent work to advanced algorithms and automation workflows. Here, we propose an algorithm for the automated selection of features driving pharmacophore model quality using SAR information extracted from validated QPhAR models. By integrating the developed method into an end-to-end workflow, we present a fully automated method that is able to derive best-quality pharmacophores from a given input dataset. Finally, we show how the QPhAR-generated models can be used to guide the researcher with insights regarding (un-)favourable interactions for compounds of interest. Full article
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17 pages, 3489 KiB  
Article
Modulation of Intestinal Corticotropin-Releasing Hormone Signaling by the Herbal Preparation STW 5-II: Possible Mechanisms for Irritable Bowel Syndrome Management
by Mohamed Elbadawi, Ramy M. Ammar, Sabine Rabini, Sabine M. Klauck and Thomas Efferth
Pharmaceuticals 2022, 15(9), 1121; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091121 - 8 Sep 2022
Cited by 3 | Viewed by 2638
Abstract
Corticotropin-releasing factor (CRF) mediates stress responses and alters the gut-brain axis, contributing to the pathogenesis of irritable bowel syndrome (IBS), which is recognized by abdominal pain accompanied by bowel habit disturbance. STW 5-II, a mixture of six herbal extracts, is clinically effective in [...] Read more.
Corticotropin-releasing factor (CRF) mediates stress responses and alters the gut-brain axis, contributing to the pathogenesis of irritable bowel syndrome (IBS), which is recognized by abdominal pain accompanied by bowel habit disturbance. STW 5-II, a mixture of six herbal extracts, is clinically effective in functional dyspepsia and IBS. Here we aimed to establish an organoid-based stress-induced IBS-like model to investigate the mechanisms of action of STW 5-II. STW 5-II (10, 20, and 30 g/mL) was applied to intestinal organoids for 24 h before being treated with CRF (100 nM) for 48 h. The effects of STW 5-II on CRF signaling were investigated using several in vitro and in silico approaches. STW 5-II activities were further explored by in silico PyRx screening followed by molecular docking of the main 52 identified compounds in STW 5-II with both CRF receptors CRFR1 and CRFR2. CRF exposure stimulated inflammation and increased proinflammatory mediators, while STW 5-II dose-dependently counteracted these effects. STW 5-II inhibited CRF-induced claudin-2 overexpression and serotonin release. Docking of the STW 5-II constituents oleanolic acid and licorice saponin G2 to CRFR1 and CRFR2, respectively, showed a good affinity. These multi-target activities support and elucidate the clinically proven efficacy of STW 5-II in disorders of gut-brain interaction. Full article
(This article belongs to the Section Natural Products)
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14 pages, 2154 KiB  
Article
A High-Affinity 64Cu-Labeled Ligand for PET Imaging of Hepsin: Design, Synthesis, and Characterization
by Ji-Hun Park, Xuran Zhang, Hyunsoo Ha, Jung Young Kim, Joon Young Choi, Kyung-Han Lee, Youngjoo Byun and Yearn Seong Choe
Pharmaceuticals 2022, 15(9), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091109 - 5 Sep 2022
Viewed by 1708
Abstract
Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of [...] Read more.
Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of hepsin. Six leucine–arginine (Leu–Arg) dipeptide derivatives (two diastereomers for each of three ligands) were synthesized and evaluated for their binding affinities and selectivity for hepsin. Based on the binding assay, a natCu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-conjugated ligand (3B) was selected for the development of a PET radioligand. [64Cu]3B was synthesized by labeling the DOTA-conjugated compound 11B with [64Cu]CuCl2 at 80 °C for 20 min. The radioligand was evaluated for prostate cancer cell binding and PET imaging in a prostate tumor mouse model. The results demonstrated that [64Cu]3B exhibited high binding to LNCaP cells, intermediate binding to 22Rv1 cells, and low binding to PC3 cells. PET studies of [64Cu]3B in mice, implanted with 22Rv1 and PC3 cells on each flank, revealed that the radioligand uptake was high and persistent in the 22Rv1 tumors over time, whereas it was low in PC3 tumors. The results of this study suggest that [64Cu]3B is a promising PET radioligand for hepsin imaging. Full article
(This article belongs to the Section Radiopharmaceutical Sciences)
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20 pages, 2772 KiB  
Article
Cu and Zn Interactions with Peptides Revealed by High-Resolution Mass Spectrometry
by Monica Iavorschi, Ancuța-Veronica Lupăescu, Laura Darie-Ion, Maria Indeykina, Gabriela Elena Hitruc and Brîndușa Alina Petre
Pharmaceuticals 2022, 15(9), 1096; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091096 - 31 Aug 2022
Cited by 2 | Viewed by 3097
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by abnormal extracellular amyloid-beta (Aβ) peptide depositions in the brain. Among amorphous aggregates, altered metal homeostasis is considered a common risk factor for neurodegeneration known to accelerate plaque formation. Recently, peptide-based drugs capable of [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by abnormal extracellular amyloid-beta (Aβ) peptide depositions in the brain. Among amorphous aggregates, altered metal homeostasis is considered a common risk factor for neurodegeneration known to accelerate plaque formation. Recently, peptide-based drugs capable of inhibiting amyloid aggregation have achieved unprecedented scientific and pharmaceutical interest. In response to metal ions binding to Aβ peptide, metal chelation was also proposed as a therapy in AD. The present study analyzes the interactions formed between NAP octapeptide, derived from activity-dependent neuroprotective protein (ADNP), amyloid Aβ(9–16) fragment and divalent metal ions such as Cu and Zn. The binding affinity studies for Cu and Zn ions of synthetic NAP peptide and Aβ(9–16) fragment were investigated by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), electrospray ion trap mass spectrometry (ESI-MS) and atomic force microscopy (AFM). Both mass spectrometric methods confirmed the formation of metal–peptide complexes while the AFM technique provided morphological and topographic information regarding the influence of metal ions upon peptide crystallization. Our findings showed that due to a rich histidine center, the Aβ(9–16) fragment is capable of binding metal ions, thus becoming stiff and promoting aggregation of the entire amyloid peptide. Apart from this, the protective effect of the NAP peptide was found to rely on the ability of this octapeptide to generate both chelating properties with metals and interactions with Aβ peptide, thus stopping its folding process. Full article
(This article belongs to the Special Issue New Applications and Developments in Synthetic Peptide Chemistry)
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13 pages, 1186 KiB  
Review
The Role of Pharmaceutical Compounding in Promoting Medication Adherence
by Maria Carvalho and Isabel F. Almeida
Pharmaceuticals 2022, 15(9), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091091 - 31 Aug 2022
Cited by 17 | Viewed by 5356
Abstract
Pharmaceutical compounding is an important component of pharmacy practice despite its low prevalence. Several therapeutic needs can be met by a compounded medicine such as dosing adjusted for pediatric patients, special drug combinations, medicines for patients allergic to a given excipient, and medicines [...] Read more.
Pharmaceutical compounding is an important component of pharmacy practice despite its low prevalence. Several therapeutic needs can be met by a compounded medicine such as dosing adjusted for pediatric patients, special drug combinations, medicines for patients allergic to a given excipient, and medicines for orphan drugs not provided by the pharmaceutical industry. Examples of such applications are provided in this review. Adherence to medication is a critical public health issue as nonadherence to pharmacotherapy has been associated with adverse outcomes and higher costs of patient care. Adherence to therapy represents a key factor in the reduction in morbidity and mortality and optimization of the use of financial resources. The role of pharmaceutical compounding in promoting medication adherence is underexploited. The customization might represent a positive reinforcement of the initiation of the treatment, while implementation and persistence might also be favored in a pharmacy setting. However, studies addressing the influence of compounding in adherence promotion are lacking in the literature. The results of such studies could support health policies including proper regulatory framework, pharmacist training, and information to health care practitioners. Full article
(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)
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11 pages, 6499 KiB  
Article
An Evaluation of the Drug Permeability Properties of Human Cadaveric In Situ Tympanic and Round Window Membranes
by Joachim G. S. Veit, Bhaskar Birru, Yong Wang, Ruby Singh, Elizabeth M. Arrigali, Ryan Park, Briggs Miller, Matthew A. Firpo, Albert H. Park and Monica A. Serban
Pharmaceuticals 2022, 15(9), 1037; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091037 - 23 Aug 2022
Cited by 9 | Viewed by 2399
Abstract
It is estimated that hearing loss currently affects more than 1.5 billion people, or approximately 20% of the global population; however, presently, there are no Food and Drug Administration-approved therapeutics or prophylactics for this condition. While continued research on the development of otoprotective [...] Read more.
It is estimated that hearing loss currently affects more than 1.5 billion people, or approximately 20% of the global population; however, presently, there are no Food and Drug Administration-approved therapeutics or prophylactics for this condition. While continued research on the development of otoprotective drugs to target this clear unmet need is an obvious path, there are numerous challenges to translating promising therapeutic candidates into human clinical testing. The screening of promising drug candidates relies exclusively on preclinical models. Current models do not permit the rapid high-throughput screening of promising drug candidates, and their relevance to clinical scenarios is often ambiguous. With the current study, we seek to understand the drug permeability properties of the cadaveric tympanic and round window membranes with the goal of generating knowledge that could inform the design and/or evaluation of in vitro organotypic models. The development of such models could enable the early high-throughput screening of topical therapeutic candidates and should address some of the limitations of currently used animal models. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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17 pages, 2623 KiB  
Article
The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
by Jean M. Nunes, Arneaux Kruger, Amy Proal, Douglas B. Kell and Etheresia Pretorius
Pharmaceuticals 2022, 15(8), 931; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080931 - 27 Jul 2022
Cited by 31 | Viewed by 21433
Abstract
We have previously demonstrated that platelet-poor plasma (PPP) obtained from patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state and contains hyperactivated platelets and considerable numbers of already-formed amyloid fibrin(ogen) or fibrinaloid microclots. Due to the substantial overlap [...] Read more.
We have previously demonstrated that platelet-poor plasma (PPP) obtained from patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state and contains hyperactivated platelets and considerable numbers of already-formed amyloid fibrin(ogen) or fibrinaloid microclots. Due to the substantial overlap in symptoms and etiology between Long COVID/PASC and ME/CFS, we investigated whether coagulopathies reflected in Long COVID/PASC—hypercoagulability, platelet hyperactivation, and fibrinaloid microclot formation—were present in individuals with ME/CFS and gender- and age-matched healthy controls. ME/CFS samples showed significant hypercoagulability as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated PPP from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed hyperactivation of platelets in ME/CFS hematocrit samples. Using a quantitative scoring system, the ME/CFS platelets were found to have a mean spreading score of 2.72 ± 1.24 vs. 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, the fibrinaloid microclot load was not as great as was previously noted in Long COVID/PASC. Fibrinaloid microclots, in particular, may contribute to many ME/CFS symptoms, such as fatigue, seen in patients with ME/CFS, via the (temporary) blockage of microcapillaries and hence ischemia. Furthermore, fibrinaloid microclots might damage the endothelium. The discovery of these biomarkers represents an important development in ME/CFS research. It also points to possible uses for treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation. Full article
(This article belongs to the Special Issue Anticoagulants and Antiplatelet Drugs)
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14 pages, 1376 KiB  
Article
Statin Use in Cancer Patients with Acute Myocardial Infarction and Its Impact on Long-Term Mortality
by Konrad Stepien, Karol Nowak, Natalia Kachnic, Grzegorz Horosin, Piotr Walczak, Aleksandra Karcinska, Tomasz Schwarz, Mariusz Wojtas, Magdalena Zalewska, Maksymilian Pastuszak, Bogdan Wegrzyn, Jadwiga Nessler and Jarosław Zalewski
Pharmaceuticals 2022, 15(8), 919; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080919 - 25 Jul 2022
Cited by 7 | Viewed by 2356
Abstract
Statin use and its impact on long-term clinical outcomes in active cancer patients following acute myocardial infarction (MI) remains insufficiently elucidated. Of the 1011 consecutive acute MI patients treated invasively between 2012 and 2017, cancer was identified in 134 (13.3%) subjects. All patients [...] Read more.
Statin use and its impact on long-term clinical outcomes in active cancer patients following acute myocardial infarction (MI) remains insufficiently elucidated. Of the 1011 consecutive acute MI patients treated invasively between 2012 and 2017, cancer was identified in 134 (13.3%) subjects. All patients were observed within a median follow-up of 69.2 (37.8–79.9) months. On discharge, statins were prescribed less frequently in MI patients with cancer as compared to the non-cancer MI population (79.9% vs. 91.4%, p < 0.001). The most common statin in both groups was atorvastatin. The long-term mortality was higher in MI patients not treated vs. those treated with statins, both in non-cancer (29.5%/year vs. 6.7%/year, p < 0.001) and cancer groups (53.9%/year vs. 24.9%/year, p < 0.05), respectively. Patient’s age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.03–1.05, p < 0.001, per year), an active cancer (HR 2.42, 95% CI 1.89–3.11, p < 0.001), hemoglobin level (HR 1.14, 95% CI 1.09–1.20, p < 0.001, per 1 g/dL decrease), and no statin on discharge (HR 2.13, 95% CI 1.61–2.78, p < 0.001) independently increased long-term mortality. In MI patients, simultaneous diagnosis of an active cancer was associated with less frequently prescribed statins on discharge. Irrespective of cancer diagnosis, no statin use was found as an independent predictor of increased long-term mortality. Full article
(This article belongs to the Special Issue Statins Use and Cancer)
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8 pages, 506 KiB  
Article
Clinical Efficacy and Safety of Antimicrobial Photodynamic Therapy in Residual Periodontal Pockets during the Maintenance Phase
by Yasunori Yamashita, Megumi Mae, Masayuki Oohira, Yukio Ozaki, Seigo Ohba, Izumi Asahina and Atsutoshi Yoshimura
Pharmaceuticals 2022, 15(8), 924; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080924 - 25 Jul 2022
Cited by 5 | Viewed by 1872
Abstract
Antimicrobial photodynamic therapy (a-PDT) in combination with scaling root planing (SRP) is more effective at improving periodontal status than SRP alone. However, the effectiveness of a-PDT in combination with irrigation for patients undergoing periodontal maintenance has not been clarified. This study evaluated the [...] Read more.
Antimicrobial photodynamic therapy (a-PDT) in combination with scaling root planing (SRP) is more effective at improving periodontal status than SRP alone. However, the effectiveness of a-PDT in combination with irrigation for patients undergoing periodontal maintenance has not been clarified. This study evaluated the efficacy and safety of a-PDT in the maintenance phase. Patients who had multiple sites with bleeding on probing (BOP) and periodontal probing depth (PPD) of 4–6 mm in the maintenance phase were treated with a split-mouth design. These sites were randomly assigned to one of two groups: the a-PDT group and the irrigation group. In the a-PDT group, the periodontal pockets were treated with light-sensitive toluidine blue and a light irradiator. In the irrigation group, the periodontal pockets were simply irrigated using an ultrasonic scaler. After 7 days, the safety and efficacy of a-PDT were assessed. The mean PPD of the a-PDT group had reduced from 4.50 mm to 4.13 mm, whereas negligible change was observed in the irrigation group. BOP significantly improved from 100% to 33% in the PDT group, whereas it hardly changed in the irrigation group. No adverse events were observed in any patients. a-PDT may be useful as a noninvasive treatment in the maintenance phase, especially in patients with relatively deep periodontal pocket. Full article
(This article belongs to the Special Issue Photodynamic Therapy 2022)
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20 pages, 1892 KiB  
Review
Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks
by Vincenzo Sorrenti, Francesca Benedetti, Alessandro Buriani, Stefano Fortinguerra, Giada Caudullo, Sergio Davinelli, Davide Zella and Giovanni Scapagnini
Pharmaceuticals 2022, 15(8), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080912 - 23 Jul 2022
Cited by 20 | Viewed by 6900
Abstract
Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence [...] Read more.
Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging. Full article
(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)
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39 pages, 7615 KiB  
Review
The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides
by Miklós Bege and Anikó Borbás
Pharmaceuticals 2022, 15(8), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080909 - 22 Jul 2022
Cited by 16 | Viewed by 5408
Abstract
Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases [...] Read more.
Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines. Full article
(This article belongs to the Section Medicinal Chemistry)
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11 pages, 3255 KiB  
Article
Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells
by Yoon-Jong Park, Han-Heom Na, In-Seo Kwon, Yu-Na Hwang, Hye-Jin Park, Tae-Hyung Kwon, Jin-Sung Park and Keun-Cheol Kim
Pharmaceuticals 2022, 15(7), 836; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070836 - 6 Jul 2022
Cited by 8 | Viewed by 2618
Abstract
Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes. In this study, [...] Read more.
Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes. In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells. CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells. CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components. Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism. These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis. Full article
(This article belongs to the Topic Advances in Anti-Cancer Drugs)
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18 pages, 4299 KiB  
Article
Suppressive Effects of Siegesbeckia orientalis Ethanolic Extract on Proliferation and Migration of Hepatocellular Carcinoma Cells through Promoting Oxidative Stress, Apoptosis and Inflammatory Responses
by Tzu-Hua Chen, Chi-Chang Chang, Jer-Yiing Houng, Tzu-Hsien Chang, Ya-Ling Chen, Chia-Chang Hsu and Long-Sen Chang
Pharmaceuticals 2022, 15(7), 826; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070826 - 3 Jul 2022
Cited by 2 | Viewed by 2478
Abstract
Previous studies have demonstrated that Siegesbeckia orientalis (SO) has a suppressive effect on the growth and migration of endometrial and cervical cancer cells. The present study examined the effect of SO ethanolic extract (SOE) on the proliferation and migration of hepatocellular carcinoma (HCC) [...] Read more.
Previous studies have demonstrated that Siegesbeckia orientalis (SO) has a suppressive effect on the growth and migration of endometrial and cervical cancer cells. The present study examined the effect of SO ethanolic extract (SOE) on the proliferation and migration of hepatocellular carcinoma (HCC) and examined the effects of SOE on non-cancerous cells using HaCaT keratinocytes as a model. The SOE effectively inhibited the proliferation of Hepa1-6 (IC50 = 282.4 μg/mL) and HepG2 (IC50 = 344.3 μg/mL) hepatoma cells, whereas it has less cytotoxic effect on HaCaT cells (IC50 = 892.4 μg/mL). The SOE treatment increased the generation of ROS in HCC, but decreased the expression of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and catalase. In contrast, it reduced intracellular ROS formation and upregulated the expression of the related antioxidant enzymes in the H2O2-stimulated HaCaT cells. The SOE intervention also down-regulated the anti-apoptotic Bcl-2 and the migration-related proteins including matrix metalloproteinases (MMPs) and β-catenin in the HCC, suggesting that SOE could promote HCC apoptosis and inhibit HCC migration. On the contrary, it reduced apoptosis and promoted the migration of the keratinocytes. Additionally, the SOE treatment significantly up-regulated the pro-inflammatory cytokines, including TNF-α, IL-6 and IL-1β, in Hepa1-6 and HepG2 cells. Conversely, it significantly decreased the expression of these cytokines in the H2O2-induced HaCaT cells. These findings indicated that SOE treatment can delay the progression of HCC by increasing oxidative stress, promoting inflammatory response, inducing cancer cell apoptosis and inhibiting their migration. It also has protective effects from pro-oxidant H2O2 in non-cancerous cells. Therefore, SOE may provide a potential treatment for liver cancer. Full article
(This article belongs to the Section Natural Products)
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26 pages, 10154 KiB  
Review
GCase Enhancers: A Potential Therapeutic Option for Gaucher Disease and Other Neurological Disorders
by Macarena Martínez-Bailén, Francesca Clemente, Camilla Matassini and Francesca Cardona
Pharmaceuticals 2022, 15(7), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070823 - 2 Jul 2022
Cited by 14 | Viewed by 4283
Abstract
Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in [...] Read more.
Pharmaceutical chaperones (PCs) are small compounds able to bind and stabilize misfolded proteins, allowing them to recover their native folding and thus their biological activity. In particular, lysosomal storage disorders (LSDs), a class of metabolic disorders due to genetic mutations that result in misfolded lysosomal enzymes, can strongly benefit from the use of PCs able to facilitate their translocation to the lysosomes. This results in a recovery of their catalytic activity. No PC for the GCase enzyme (lysosomal acid-β-glucosidase, or glucocerebrosidase) has reached the market yet, despite the importance of this enzyme not only for Gaucher disease, the most common LSD, but also for neurological disorders, such as Parkinson’s disease. This review aims to describe the efforts made by the scientific community in the last 7 years (since 2015) in order to identify new PCs for the GCase enzyme, which have been mainly identified among glycomimetic-based compounds. Full article
(This article belongs to the Special Issue Carbohydrate-Based Drugs)
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17 pages, 1276 KiB  
Article
Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict PET Image Quality of Three Generations EGFR TKI in Advanced-Stage NSCLC Patients
by I. H. Bartelink, E. A. van de Stadt, A. F. Leeuwerik, V. L. J. L. Thijssen, J. R. I. Hupsel, J. F. van den Nieuwendijk, I. Bahce, M. Yaqub and N. H. Hendrikse
Pharmaceuticals 2022, 15(7), 796; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070796 - 27 Jun 2022
Cited by 8 | Viewed by 2808
Abstract
Introduction: Epidermal growth factor receptor (EGFR) mutated NSCLC is best treated using an EGFR tyrosine kinase inhibitor (TKI). The presence and accessibility of EGFR overexpression and mutation in NSCLC can be determined using radiolabeled EGFR TKI PET/CT. However, recent research has shown a [...] Read more.
Introduction: Epidermal growth factor receptor (EGFR) mutated NSCLC is best treated using an EGFR tyrosine kinase inhibitor (TKI). The presence and accessibility of EGFR overexpression and mutation in NSCLC can be determined using radiolabeled EGFR TKI PET/CT. However, recent research has shown a significant difference between image qualities (i.e., tumor-to-lung contrast) in three generation EGFR TKIs: 11C-erlotinib, 18F-afatinib and 11C-osimertinib. In this research we aim to develop a physiological pharmacokinetic (PBPK)-model to predict tumor-to-lung contrast and as a secondary outcome the uptake of healthy tissue of the three tracers. Methods: Relevant physicochemical and drug specific properties (e.g., pKa, lipophilicity, target binding) for each TKI were collected and applied in established base PBPK models. Key hallmarks of NSCLC include: immune tumor deprivation, unaltered tumor perfusion and an acidic tumor environment. Model accuracy was demonstrated by calculating the prediction error (PE) between predicted tissue-to-blood ratios (TBR) and measured PET-image-derived TBR. Sensitivity analysis was performed by excluding each key component and comparing the PE with the final mechanistical PBPK model predictions. Results: The developed PBPK models were able to predict tumor-to-lung contrast for all EGFR-TKIs within threefold of observed PET image ratios (PE tumor-to-lung ratio of −90%, +44% and −6.3% for erlotinib, afatinib and osimertinib, respectively). Furthermore, the models depicted agreeable whole-body distribution, showing high tissue distribution for osimertinib and afatinib and low tissue distribution at high blood concentrations for erlotinib (mean PE, of −10.5%, range −158%–+190%, for all tissues). Conclusion: The developed PBPK models adequately predicted the image quality of afatinib and osimertinib and erlotinib. Some deviations in predicted whole-body TBR lead to new hypotheses, such as increased affinity for mutated EGFR and active influx transport (erlotinib into excreting tissues) or active efflux (afatinib from brain), which is currently unaccounted for. In the future, PBPK models may be used to predict the image quality of new tracers. Full article
(This article belongs to the Special Issue Computational Methods in the Design of Anticancer Drugs)
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12 pages, 1617 KiB  
Article
64Cu-SAR-Bombesin PET-CT Imaging in the Staging of Estrogen/Progesterone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients: Safety, Dosimetry and Feasibility in a Phase I Trial
by Keith Wong, Gemma Sheehan-Dare, Andrew Nguyen, Bao Ho, Victor Liu, Jonathan Lee, Lauren Brown, Rachel Dear, Lyn Chan, Shikha Sharma, Alessandra Malaroda, Isabelle Smith, Elgene Lim and Louise Emmett
Pharmaceuticals 2022, 15(7), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070772 - 22 Jun 2022
Cited by 9 | Viewed by 2857
Abstract
Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential [...] Read more.
Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy samples. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. <3). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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18 pages, 1847 KiB  
Review
Roles of Bacterial Mechanosensitive Channels in Infection and Antibiotic Susceptibility
by Margareth Sidarta, Luna Baruah and Michaela Wenzel
Pharmaceuticals 2022, 15(7), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070770 - 21 Jun 2022
Cited by 10 | Viewed by 3550
Abstract
Bacteria accumulate osmolytes to prevent cell dehydration during hyperosmotic stress. A sudden change to a hypotonic environment leads to a rapid water influx, causing swelling of the protoplast. To prevent cell lysis through osmotic bursting, mechanosensitive channels detect changes in turgor pressure and [...] Read more.
Bacteria accumulate osmolytes to prevent cell dehydration during hyperosmotic stress. A sudden change to a hypotonic environment leads to a rapid water influx, causing swelling of the protoplast. To prevent cell lysis through osmotic bursting, mechanosensitive channels detect changes in turgor pressure and act as emergency-release valves for the ions and osmolytes, restoring the osmotic balance. This adaptation mechanism is well-characterized with respect to the osmotic challenges bacteria face in environments such as soil or an aquatic habitat. However, mechanosensitive channels also play a role during infection, e.g., during host colonization or release into environmental reservoirs. Moreover, recent studies have proposed roles for mechanosensitive channels as determinants of antibiotic susceptibility. Interestingly, some studies suggest that they serve as entry gates for antimicrobials into cells, enhancing antibiotic efficiency, while others propose that they play a role in antibiotic-stress adaptation, reducing susceptibility to certain antimicrobials. These findings suggest different facets regarding the relevance of mechanosensitive channels during infection and antibiotic exposure as well as illustrate that they may be interesting targets for antibacterial chemotherapy. Here, we summarize the recent findings on the relevance of mechanosensitive channels for bacterial infections, including transitioning between host and environment, virulence, and susceptibility to antimicrobials, and discuss their potential as antibacterial drug targets. Full article
(This article belongs to the Special Issue Mechanisms of Antibiotic Action and Resistance)
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28 pages, 1642 KiB  
Review
Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production
by Caroline Bayart, Angélique Mularoni, Nada Hemmani, Soumeya Kerachni, Joachim Jose, Patrice Gouet, Joseph Paladino and Marc Le Borgne
Pharmaceuticals 2022, 15(6), 756; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060756 - 17 Jun 2022
Cited by 8 | Viewed by 5732
Abstract
Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining [...] Read more.
Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector. Full article
(This article belongs to the Section Biopharmaceuticals)
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34 pages, 4071 KiB  
Review
Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis
by Fabian Krutzek, Klaus Kopka and Sven Stadlbauer
Pharmaceuticals 2022, 15(6), 747; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060747 - 14 Jun 2022
Cited by 20 | Viewed by 4785
Abstract
Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been [...] Read more.
Immune checkpoint inhibitor (ICI) therapy has emerged as a major treatment option for a variety of cancers. Among the immune checkpoints addressed, the programmed death receptor 1 (PD-1) and its ligand PD-L1 are the key targets for an ICI. PD-L1 has especially been proven to be a reproducible biomarker allowing for therapy decisions and monitoring therapy success. However, the expression of PD-L1 is not only heterogeneous among and within tumor lesions, but the expression is very dynamic and changes over time. Immunohistochemistry, which is the standard diagnostic tool, can only inadequately address these challenges. On the other hand, molecular imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) provide the advantage of a whole-body scan and therefore fully address the issue of the heterogeneous expression of checkpoints over time. Here, we provide an overview of existing PET, SPECT, and optical imaging (OI) (radio)tracers for the imaging of the upregulation levels of PD-1 and PD-L1. We summarize the preclinical and clinical data of the different molecule classes of radiotracers and discuss their respective advantages and disadvantages. At the end, we show possible future directions for developing new radiotracers for the imaging of PD-1/PD-L1 status in cancer patients. Full article
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